The limited proliferative potential of normal human cells in culture has provided an important model for the study of aging at the cellular level. The model has been validated by various data, including the fact that cells from individuals that exhibit premature aging have lower proliferative potential. Studies have clearly shown that cellular aging is due to active processes which result in inhibition of DNA synthesis and other changes in gene expression. When the processes that lead to cellular aging are disrupted, cells escape senescence and are able to divide indefinitely. This program project will take a molecular approach to the study of cellular aging. We will investigate the various changes in gene expression that occur as cells age in vitro, including those that lead to inhibition of DNA synthesis. We will also investigate the genetic defects that result in cellular immortalization and premature aging. This program is organized around four individual interacting scientific projects served by three cores, two technical and one administrative.